DESCRIPTION: Impaired pulmonary function limits the total radiation dose and volume of irradiation to the lung, and the optimal use of chemotherapy with radiation. We found that radiation-induced expression of cell adhesion molecules (CAMs) in the lung results in inflammatory cell adhesion to the pulmonary microvasculature. Leukocytes adhere to the vascular endothelium within hours of irradiation. Leukocyte adhesion to the endothelium requires the expression of CAMs on the intraluminal surface of the vascular endothelium. To determine the biological significance of leukocyte adhesion in the irradiated lung, we treated ICAM-knock-out mice (ICAM -/-) with thoracic irradiation, and found no accumulation of leukocytes in the irradiated lung. Conversely, ICAM +/+ mice developed wide areas of inflammatory cell infiltration in the irradiated lung. We hypothesize that x-ray-mediated CAM induction is an initial event that results in the propagation of inflammation and consequent tissue injury. The mechanism of induction of CAMs following irradiation is transcriptional activation of the promoter region of these genes. Our preliminary data indicate that transcription factors bind to the cis-acting elements from E-selectin and ICAM-1 is a proteoglycan that is expressed in the lung as early as 18 hours after exposure to does as low as 2 Gy. ICAM expression persisted for several days after irradiation. These cell adhesion molecules initiate leukocyte adhesion to the vascular endothelium and activate these inflammatory cells. We will determine the mechanisms of radiation-mediated transcriptional induction of the ICAM-1 gene. We will also determine whether CAM expression is required for the pathogenesis of radiation-mediated tissue injury.